Inflammation and nutritional status indicators as prognostic indicators for patients with locally advanced gastrointestinal stromal tumors treated with neoadjuvant imatinib

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal derived tumours and most patients have mutations in the c-kit or platelet derived growth factor receptor alpha (PDGFRA) gene [1, 2]. Currently, the preferred treatment for GIST patients is surgical resection, with the goals of obtaining R0 margins, avoiding intraoperative tumour rupture and maximising preservation of organ function [3, 4]. Nevertheless, a growing number of studies have found that direct surgical resection is difficult for patients with specific sites (oesophagogastric junction, low rectum, duodenum) and large tumour diameters [5, 6]. Recently, imatinib, a small molecule tyrosine kinase inhibitor (TKI), has been widely used as an adjuvant therapy for GIST patients after surgery as it can inhibit cell growth and promote apoptosis by blocking tyrosine kinase [7, 8]. Several retrospective studies have found that neoadjuvant treatment with preoperative imatinib can be attempted in patients with locally advanced GIST (LA-GIST) [9‐11]. Meanwhile, a prospective study of 63 patients with LA-GIST (RTOG 0132) found that surgical resection after 8–12 weeks of preoperative neoadjuvant imatinib (600 mg/d) resulted in an R0 resection rate of 77% and a 5-years overall survival rate of 77% [12]. In addition, several multicentre prospective studies have shown the same results, suggesting that preoperative neoadjuvant therapy with imatinib is effective in the treatment of LA-GIST and has a good “down-staging” effect, improving the R0 resection rate, safety of surgery and facilitating the preservation of organ function [13, 14].

Unfortunately, not all patients benefit from those treatments, and some of them develop recurrent metastases within a short period of time after treatment. Currently, the risk of recurrence after neoadjuvant therapy for LA-GIST is assessed by the National Institutes of Health (NIH) (2008 modified version), the Armed Forces Institute of Pathology (AFIP) criteria, primary tumour site, tumour diameter and mitotic index [15]. However, these assessment indicators are considered only from the perspective of the original GIST and ignore the impact of the patient's inflammatory and nutritional status on the tumour during neoadjuvant therapy.

Presently, inflammation plays an important role in the pathogenesis of malignant tumors, and the latest view is that tumor-related inflammation is considered to be the seventh characteristic of tumors [16, 17]. Numerous studies have found that the systemic inflammatory response can disrupt the host's immune response and promote tumour cells to escape from immune surveillance, which further promotes the development of angiogenesis, invasion and metastasis [18, 19]. At the same time, previous studies have found that the nutritional status of the tumour patient is one of the key factors influencing the progression of the tumour [20, 21]. The systemic immune-inflammatory index (SII) is a comprehensive measure of the body's systemic inflammatory and immune status consisting of peripheral blood neutrophils, lymphocytes and platelets [22]. Accumulating evidence has revealed that SII is closely related to the prognosis of various malignant tumors [22‐24].

Our previous study also found that 10.09% of newly diagnosed GIST patients had malnutrition, and most of them were middle- and high-risk types [25]. Further follow-up found that the nutritional status of patients was also closely related to prognosis. Therefore, we hypothesise that poor nutritional status during neoadjuvant therapy in patients with LA-GIST may also be strongly associated with poor prognosis. The prognostic nutritional index (PNI), as a simple and feasible nutritional assay, formed based on the combination of lymphocyte count and albumin levels, has been shown to be associated with the prognosis of various malignancies and is widely used to assess the prediction of the efficacy of neoadjuvant therapy and the assessment of prognosis in cancer patients [26, 27].

In previous studies we have found that a new scoring system combining SII with PNI in immunotherapy for locally progressive gastric cancer [28] and in conversion therapy for advanced gastric cancer [29] has good diagnostic value in predicting the efficacy and assessing prognosis. However, previous studies have generally used a single haematological index, including SII [30] and PNI [31], and few studies have used SII in combination with PNI to assess the evaluation of efficacy and prediction of prognosis in LA-GIST patients after neoadjuvant therapy with imatinib. Therefore, in this study, we evaluated the predictive value of the pre-treatment SII-PNI score on the efficacy and prognosis of patients with LA-GIST receiving neoadjuvant therapy with imatinib.

In recent years, with the rapid development of surgical techniques and multimodal therapies such as TKI molecular targeting drugs, the clinical outcomes and quality of life of GIST patients have improved significantly [3]. Nowadays, neoadjuvant treatment with imatinib for patients with LA-GIST has attracted much attention, with the following advantages [33, 35]: firstly, it can reduce the tumor volume and decrease the clinical stage; secondly, it can also reduce the scope of surgery and avoid unnecessary combined organ resection, reducing the risk of surgery and also increasing the chance of radical resection; in addition, it can protect the structure and function of important organs for tumors in specific sites; finally, for patients with large tumor diameter and high risk of intraoperative rupture, neoadjuvant treatment can reduce the possibility of drug-induced dissemination therapy. However, not all patients with LA-GIST benefit from this, with 10–20% of patients experiencing progression after 3 years of treatment [36]. In our cohort, we observed disease progression of 14.04% at 3 years after neoadjuvant imatinib treatment, which is consistent with previous studies [11, 36]. Currently, the common approach to predicting recurrence for LA-GIST is the 2008 revised NIH, AFIP and other guideline consensus, but these are only assessed from the perspective of postoperative pathology and do not take into account the dynamic changes in inflammatory and nutritional status of patients during neoadjuvant therapy [15].

Numerous studies have found that the biological behaviour of malignant tumourigenesis, development and invasion depends not only on the malignant characteristics of the tumour cells, but also on the tumour microenvironment [16, 18]. Inflammatory cells are considered to be an important component of the tumour microenvironment, and their mediated inflammatory response promotes invasion and metastasis by disrupting the immune response and further leading to immune escape of tumour cells [37]. Currently, a growing number of studies have found that inflammatory cells in peripheral blood can migrate through the body circulation to act in local tumour tissues, and therefore systemic inflammatory markers can be used to predict tumour prognosis in the tumour microenvironment in relation to the immune response [38]. The SII has received increasing attention as a more comprehensive measure of the status of the systemic inflammatory response, and several studies have confirmed its value in predicting tumour prognosis and outcome [18, 19, 23]. Besides, the nutritional status of GIST patients has received increasing attention in recent years. Our previous studies have demonstrated that nutritional status of GIST patients is a risk factor affecting the prognosis whether at the initial diagnosis or after surgery [22, 39]. The PNI is an index calculated from serum albumin and peripheral blood lymphocytes that provides a comprehensive reflection of the patient's nutritional status and immune function [26, 27]. To the best of knowledge, this is the first study to demonstrate the prognosis prediction of SII combined with PNI in patients with LA-GIST after neoadjuvant imatinib.

Our study showed that patients who developed recurrence had higher SII and lower PNI than the non-recurrence group at baseline, but this difference was less pronounced after neoadjuvant therapy. Meanwhile, we also found that the SII-PNI score correlated with pathological response after neoadjuvant chemotherapy, with the higher the score at baseline, the worse the pathological response in LA-GIST patients, which was consistent with our previous study [28, 29]. We speculate that the reasons for this outcome may include: firstly, elevated SII prior to neoadjuvant therapy indicates the presence of an inflammatory microenvironment that promotes tumor invasion and metastasis, whereas reduced PNI indicates poorer immune function and nutritional status, further promoting the formation of an inflammatory microenvironment as it was described by Yamanaka et al. [40]. Furthermore, epithelial-mesenchymal transition (EMT) mediated by the local inflammatory microenvironment of the tumor promotes tumor cell escape and resistance to therapeutic agents, which in turn affects the pathological response to neoadjuvant therapy in patients with LA-GIST [41, 42].

In recent years, there has also been increasing interest in the impact of SII and PNI on the prognosis of GIST patients. A retrospective study involving 431 GIST patients found that compared with the low PNI group (PNI < 47.45), the recurrence-free survival (RFS) of the high PNI group (PNI ≥ 47.45) was significantly prolonged (the 5-years RFS rates were 89.9% and 70.8%, respectively, P < 0.001) [31]. Interestingly, Elif Yuce et al. [43] found that PNI was not a risk factor for the prognosis of GIST patients. Furthermore, As Dolan et al. [44] published a retrospective analysis including 160 patients who underwent GIST surgery, the authors demonstrated that SII could be used as a prognostic predictor. Similar results were obtained in another retrospective analysis that included 45 GIST patients [30]. In this study, we also assessed the relationship between SII-PNI scores and neoadjuvant treatment recurrence in patients with LA-GIST. The 3-years RFS for patients with SII-PNI scores of 0 was 100.00% compared to 84.62% and 45.45% for patients with scores of 1 and 2 respectively, with significant differences between the three groups. The possible mechanism of SII-PNI predicting prognosis are as the followings: firstly, elevated neutrophils significantly inhibit lymphokine-activated killer cell-mediated cytotoxic effects, thereby down-regulating the patient's anti-tumor cell immune response and thus promoting tumor cell proliferation and migration [45, 46]; secondly, platelets promote tumour growth by secreting tumour growth factors such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Platelets can also play an integrative role in the process of tumor cell metastasis, causing tumor cells to evade the host immune system, thus protecting tumor cells from being easily recognized and facilitating tumor cell dissemination [47]; furthermore, lymphocytopenia suggests a decrease in the body's immune function, inducing apoptosis of tumor-specific T cells and inhibiting the activation and proliferation of T cells, further promoting the proliferation and migration of tumor cells [48, 49]; finally, systemic inflammatory responses exacerbate malnutrition and decreased body function in patients with malignancy, promoting poor prognosis in patients with malignancy [40].

It is noteworthy that a few limitations of current research also exist. Firstly, this study was a single-centre retrospective study with a relatively small number of patients included, which may have been subject to selection bias. Secondly, this study only analysed the relationship between SII-PNI scores and recurrence in LA-GIST patients, and not the overall survival time of patients. Therefore, more large-sample, prospective, multicentre studies are needed for validation in order to determine the predictive value of the parameters examined in the study.

In conclusion, our study suggests that systemic inflammation and nutritional status are equally important in the tumourigenesis of LA-GIST cases. This study was the first to show that the SII-PNI score based on peripheral blood counts in LA-GIST patients is a promising predictor of pathological response and recurrence outcome after neoadjuvant therapy. These findings may facilitate the development of treatment strategies and clinical risk stratification.